The Case for beta-Adrenergic Blockade as Prophylaxis Against Perioperative
Cardiovascular Morbidity and Mortality


Author Information
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#aainfo>   Craig H.
Selzman, MD; Stephanie A. Miller, MD; Michael A. Zimmerman, MD; Alden H.
Harken, MD
Perioperative morbidity and mortality are frequently cardiac in origin. Many
studies have prospectively attempted to define risk factors for cardiac
ischemic events. Although we can now identify high-risk patients, optimal
cardioprotective management strategies remain unclear. Treatment with
beta-adrenergic antagonists decreases myocardial oxygen consumption and is
generally well tolerated. This article reviews the physiologic and clinical
basis for using these agents as prophylaxis against cardiovascular events in
high-risk surgical patients.
Arch Surg. 2001;136:286-290




SSA0005
In patients with known cardiovascular disease, myocardial ischemia remains
the principal cause of morbidity and mortality after cardiac and noncardiac
surgery. As our population ages, this problem will affect nearly 35 million
people, with a yearly estimated cost of more than $20 billion. 1
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r1>  Numerous
investigators 2 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r2> , 3
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r3>  have prospectively
attempted to identify factors that place patients at high risk. A potpourri
of historical factors have been implicated, including age, recent myocardial
infarction, congestive heart failure, active angina, ventricular
dysrhythmias, diabetes, and the type and urgency of the operation. Although
we generally can identify patients at high risk for perioperative
cardiovascular events, it remains unclear what we should do with this
information. No randomized, prospective trial, to our knowledge, has
demonstrated the benefit or efficacy of preoperative myocardial
revascularization. Indeed, excessive preoperative cardiac screening and
subsequent intervention might prove detrimental. 4
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r4>  The Coronary Artery
Revascularization Prophylaxis trial is currently enrolling patients to
answer this question. 5
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r5>  In the meantime, we
are left with the dilemma of how best to reduce cardiovascular complications
in patients undergoing noncardiac surgery. The purpose of the present
article is to review the physiologic and clinical basis for beta-adrenergic
antagonism in surgical patients.



PHYSIOLOGIC BASIS FOR ADRENERGIC ANTAGONISM



Neurohormonal Stress of Surgery

The neurohormonal stress of elective surgery begins well before the skin
incision. Activation of the hypothalamus-pituitary-adrenal axis is initiated
by just scheduling the operation and persists throughout surgery until at
least a week after surgery. This period, often referred to as the
adrenergic-corticoid phase, is defined by hypercatabolism and hypersecretion
of neuroendocrine substances. One of the earliest events after afferent
stimulation of the hypothalamus is the release of corticotropin and
subsequent elaboration of cortisol. Concomitant with adrenal cortical
stimulation is medullary activation by the sympathetic nervous system and
release of catecholamines. 6
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r6>  Although the
evolutionary intent of these stress reactions is clear in the jungle, these
same survival responses, especially if dysregulated, might threaten a
debilitated patient with poor reserve. Adrenergic receptors are located in
virtually every organ, orchestrating the stress response. In the human
heart, alpha1-, beta1-, and beta2-adrenergic receptors promote several
biologic responses, including inotropy, chronotropy, myocyte apoptosis, and
direct myocyte toxicity. Left unabated, chronic adrenergic stimulus results
in pathologic ventricular remodeling, acute coronary syndromes,
arrythmogenesis, and end-stage cardiomyopathy.
Myocardial Oxygen Consumption

Surgery itself obligates myocardial work; patients with coronary artery
disease are unable to meet this increased demand. Myocardial ischemia within
48 hours of surgery, either clinically occult or overt, confers a 9-fold
increase in risk of unstable angina, nonfatal myocardial infarction, and
cardiac death. 7 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r7>
Therapeutic strategies to attenuate this ischemic insult must therefore
favorably manipulate the physiologic balance of myocardial oxygen supply and
demand.
Myocardial oxygen consumption ultimately reflects the utilization of
mitochondrial adenosine triphosphate. As such, conditions that deplete
myocardial adenosine triphosphate levels inversely increase oxygen uptake.
In 1969, Braunwald 8 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r8>
presented a unified concept of the determinants of myocardial oxygen
consumption. Examining nearly a century of experimental studies and a decade
of his own work, he elucidated 8 key componentsand their relative
contributionsof myocardial oxygen consumption. He concluded that the major
contributors to cardiac work are heart rate, developed force, and
contractile state. In fact, he demonstrated that the catecholamine-induced
increase in myocardial oxygen consumption was not so much a function of
their direct metabolic effect but rather of their effect on myocardial
contractile activity.
Modern interpretation of the thesis by Braunwald 8
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r8>  has focused on 4
prime determinants of oxygen demand: heart rate, preload, afterload, and
contractility. Elevated heart rate is associated with shortening of
diastolic perfusion (nutrient and oxygen) time. Wall stress (as defined by
Laplace's law) accounts for the contributions of preload and afterload to
myocardial oxygen demand. Enhanced contractility affects the equation by
changing the relationship between developed pressure and ventricular volume.
Cumulatively, a clinical index of myocardial oxygen demand is represented by
the "rate-pressure product" (heart rate mean arterial pressure). This is one
basis for the anesthestic goal of maintaining a patient's rate-pressure
product within 10% of the preoperative value.
Catecholamines and Myocardial Work

Catecholamines conspire to increase each of the 4 major determinants of
myocardial oxygen consumption. The chronotropic effects of beta1-receptor
stimulation are well recognized. Macrovascular and microvascular tone are,
in part, controlled by adrenergic tone. alpha1-Receptor stimulationship
promotes venoconstriction, thus affecting afterload and preload. Figure 1
<http://archsurg.ama-assn.org/issues/v136n3/fig_tab/ssa0005_f1.html>
graphically depicts the relationship among heart rate, blood pressure, and
myocardial oxygen consumption (area integrated under each curve). Compared
with the basal state, stimulation with epinephrine increases heart rate
(cycles per second), vascular resistance (peak pressure), and contractility
(steeper slope, ie, an increase in the developed pressure per time).
Cumulatively, these catecholamine effects result in an increase in
myocardial oxygen consumption.



CLINICAL BASIS FOR ADRENERGIC ANTAGONISM



Early Studies of Perioperative beta-Adrenergic Blockade

Just as adrenergic stimulation can magnify each determinant of myocardial
oxygen demand, adrenergic antagonism can attenuate each variable. Individual
studies have associated beta-adrenergic blockade–mediated decreases in
myocardial oxygen consumption with a reduction in heart rate, wall tension,
and contractility. As a clinical correlate, several studies demonstrate that
beta-adrenergic blockade can also decrease perioperative myocardial
ischemia. 9 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r9>  Yet, few
dataand until recently, no randomized trialshave positively correlated this
physiologic effect with clinical outcomes.
The initial study 10 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r10>
demonstrating the beneficial effect of adrenergic antagonism on
perioperative morbidity and mortality involved patients with hypertension
taking propranolol hydrochloride who seemed to be at risk for propranolol
withdrawl syndrome at the time of surgery ( Table 1
<http://archsurg.ama-assn.org/issues/v136n3/fig_tab/ssa0005_t1.html> ).
Thirteen patients were treated with continuous propranolol infusions after
abdominal operations. They strictly monitored serum drug levels, noticed no
withdrawal, and reported no perioperative cardiovascular complications.
Perioperative propranolol administration subsequently proved to be
cardioprotective during cardiac surgery. In another study, 11
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r11>  50 patients
undergoing coronary artery bypass surgery were randomized to receive
propranolol or placebo 24 to 48 hours before surgery and continuing for 30
days after surgery. Propranolol treatment significantly decreased the
rate-pressure product on induction of anesthesia and sternotomy.
Cumulatively, patients taking beta-adrenergic blocking agents had less need
for antihypertensive therapy after surgery and experienced reduced incidence
and frequency of supraventricular and ventricular arrhythmias and no
mortality. Although these studies are small, they suggest the clinical
relevance of beta-adrenergic blocking agent–dependent decreases in
myocardial oxygen consumption as it pertains to myocardial ischemia and
possibly arrhythmogenesis.
During the 1990s, several more retrospective and case-controlled studies
promoted perioperative beta-adrenergic blockade. Stone and colleagues 9
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r9>  gave untreated
hypertensive patients undergoing abdominal and vascular surgery a single
oral dose of labetalol hydrochloride or atenolol. Whereas 11 of 39 control
patients exhibited intraoperative myocardial ischemia, tachycardia and
electrocardiographic evidence of ischemia was observed in only 2 of 89
treated patients. 9 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r9>
This study was corroborated in another group of vascular surgery patients
given metoprolol, 50 mg, before surgery. 12
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r12>  Compared with
controls, treated patients had less frequent and shorter periods of
intraoperative silent ischemia. 12
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r12>  These studies did
not correlate intraoperative ischemia with cardiovascular outcome. In a
retrospective study 13
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r13>  from the University
of Oregon, factors associated with perioperative myocardial infarction were
analyzed in more than 2000 vascular surgery patients. Use of beta-adrenergic
blocking agents conferred a 50% reduction in the relative risk of
perioperative myocardial infarction. Although this risk reduction is
impressive, a surprisingly high number of patients who experienced
myocardial infarction were taking beta-adrenergic blocking agents (30%). As
with the previous studies, outcomes relating the perioperative event to
ultimate cardiovascular morbidity and mortality were not reported.
Randomized Trials of Perioperative beta-Adrenergic Blockade

In 1996, Mangano and colleagues 14
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r14>  published the first
randomized, prospective trial examining the effect of the cardioselective
agent, atenolol, on cardiovascular morbidity and mortality after noncardiac
surgery. Two hundred patients at a Veterans Affairs Medical Center
undergoing vascular, abdominal, orthopedic, and neurosurgical procedures
were randomized to receive placebo (n = 101) or treatment with atenolol (n =
99). Eligible patients were those with previous myocardial infarction,
typical angina, or atypical angina with a positive stress test result or
those at risk for coronary artery disease (2 traditional risk factors).
Treated patients received atenolol, 5 to 10 mg, intravenously before surgery
and atenolol, 5 to 10 mg, intravenously twice daily or 50 to 100 mg orally
until discharge or 7 days maximum. Goals of treatment included a heart rate
of 55 to 65 beats per minute (bpm) and systolic blood pressure of less than
100 to 110 mm Hg. The primary end point was all-cause mortality over a
2-year period (99% follow-up); secondary end points included myocardial
infarction, congestive heart failure, unstable angina, and myocardial
revascularization.
Overall mortality was less in the atenolol vs the control group at 2 years
(9% vs 21%). Risk reduction was evident within the first 6 months (no
cardiac events in the atenolol group vs 12% in the control group), and the
advantage was sustained throughout follow-up. Although the results of this
study suggest a role for perioperative atenolol use in providing long-term
cardioprotection, these results must be interpreted with several caveats.
First, the placebo group suggested a trend toward sicker patients. Second,
surgical patients in a Veterans Affairs facility might not be representative
of the population at large. Finally, more patients in the treatment group
were taking beta-adrenergic blocking agents and angiotensin-converting
enzyme inhibitors during follow-up. Although atenolol treatment was
associated with less perioperative ischemia, beta-adrenergic blockade did
not significantly reduce the incidence of in-hospital myocardial infarction
or cardiac mortality. 17
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r17>  Possibly, the
observed decrease in cardiac mortality had nothing to do with the 7 days of
atenolol treatment but rather the 6 to 24 months of treatment with other
risk-reducing agents.
In 1999, Poldermans and colleagues 15
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r15>  published the
second major randomized, controlled trial evaluating perioperative
beta-adrenergic blockade. This study attempted to define a subgroup of
patients who might benefit maximally from adrenergic antagonism. The study
by Mangano and colleagues 14
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r14>  reported an
extremely low incidence of perioperative cardiac events (3%). This
observation was due, in part, to the inclusion of patients with known
coronary artery disease and those with only coronary risk factors undergoing
a diverse array of operations. Conversely, the study by Poldermans and
colleagues 15 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r15>  was
limited to high-risk patients undergoing only abdominal or infrainguinal
arterial procedures. Patients were included if they had 1 or more risk
factors (previous myocardial infarction, angina, history of or current
congestive heart failure, age >70 years, treated ventricular arrhythmia,
hypertension, or diabetes) and a positive result on dobutamine
echocardiography. One hundred twelve patients were randomized to placebo (n
= 53) or treatment with the cardioselective (beta1) adrenergic receptor
antagonist, bisoprolol (n = 59). Treatment with bisoprolol, 5 to 10 mg
orally, was started a least 1 week before surgery and was continued for 30
days after surgery. The primary end points were myocardial infarction and
cardiac mortality during the 30 days after surgery.
Cardiac events were observed in 34% of the control group compared with only
3.4% of the bisoprolol group. In addition, there were no myocardial
infarctions in the treatment arm. These significant differences prompted the
safety committee to suspend the trial (original recruitment goal was 266
patients). Although impressive, these results must also be interpreted with
several caveats. This was a nonblinded study with fairly low patient
numbers. Two groups of patients were excluded from randomization: those
already taking beta-adrenergic blocking agents and those with extensive
wall-motion abnormalities on stress echocardiography. The authors offered no
explanation for the 7.5% cardiac mortality rate seen in 53 patients already
receiving beta-adrenergic blockade. Intuitively, it seems that these
patients should also have been protected. Of 8 patients with extensive
wall-motion defects (defined by wall-motion index), 4 underwent coronary
artery bypass (2 died) and 4 underwent vascular surgery with beta-adrenergic
blockade (1 perioperative myocardial infarction). Nonrandomization aside,
inclusion of these "fringe" patients would not significantly change the
overal impact of the study. These patients were clearly sicker and more
homogeneous than those in the study by Mangano and colleagues. 14
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r14>  As such, the
conclusion that perioperative beta-adrenergic blockade is cardioprotective
in high-risk patients undergoing major vascular surgery seems valid.



CONCLUSIONS AND RECOMMENDATIONS



Consistent in the surgical literature is that use of beta-adrenergic
blocking agents by patients with cardiopulmonary disease is well tolerated.
Most patients could achieve the hemodynamic goals of heart rate and systolic
blood pressure without developing bronchospasm or congestive heart failure.
Although the bisoprolol study excluded patients with asthma, current
recommendations do not automatically exclude patients with reactive airway
disease from receiving beta-adrenergic blocking agents. In fact, judicious
titration of cardioselective adrenergic antagonists seems to be indicated in
patients with mild to moderately severe asthma and coronary artery disease.
18 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r18>  Likewise, the
historic contraindication of beta-adrenergic blockade in patients with
reduced left ventricular function and congestive heart failure has been
revisited in the past decade. Cardioselective and newer-generation
beta-adrenergic blocking agents have been successfully used in patients with
New York Heart Association class II and III symptoms. 19
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r19>
Although therapeutic delivery of adrenergic antagonists is often premised on
decreasing catecholamine-induced myocardial oxygen consumption, several
other mechanisms likely contribute to their cardioprotective effect.
Catecholamines instigate and perpetuate vascular injury by promoting
endothelial dysfunction, platelet aggregation, endovascular adhesion
molecule release, hypercoagulability, hypertension, and direct myocyte
toxicity. beta-Adrenergic blockade, experimentally and epidemiologically,
can reverse many of these effects. In addition, use of beta-adrenergic
blocking agents might inhibit apoptosis and platelet deposition, thus
stabilizing the vulnerable coronary plaque. Finally, although use of
beta-adrenergic blocking agents has often been associated with dyslipidemias
(particularly reduction in high-density lipoprotein levels), changes in
lipid profiles are usually small and outweighed by the cumulative
cardioprotective effect of these agents.
There are several different approaches to providing perioperative
cardioprotection. Although many of these strategies remain experimental or
anecdotal, others have been studied in controlled trials. 20
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r20>  The former category
includes synthetic oxygen carriers, antiplatelet agents, bradykinin
antagonists, adenosine, opioid receptor agonists, and inflammatory mediator
antagonists. Traditional perioperative pharmacotherapy has often included
calcium channel blockers, nitrates, and alpha2-adrenoceptor agonists. As
with beta-adrenergic blocking agents, these agents affect the vasculature
and myocardial oxygen consumption at several levels. For example, use of
nitroglycerin decreases demand by its venodilatory properties. In addition,
nitroglycerin is also a coronary vasodilator and direct nitric oxide donor.
Although use of nitroglycerin intuitively makes sense and is supported in
several studies, results of a conflicting study 21
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r21>  suggest that
nitroglycerin use has no effect on intraoperative ischemia and might even be
deleterious. While we support the use of adrenergic antagonists, it would be
naive to suggest that use of these agents, alone, will independently confer
protection. beta-Adrenergic blockade should be part of a comprehensive
pharmacologic strategy that includes other drugs, such as aspirin,
angiotensin-converting enzyme inhibitors, and hydroxymethyl glutaryl
coenzyme A reductase inhibitors (statins), that reduce the risk of
cardiovascular events.
In gratifyingly intuitive fashion, perioperative administration of
beta-adrenergic blocking agents for the prevention of surgical
cardiovascular morbidity and mortality is based on physiologic principles
and is supported by randomized, prospective trials. In 1996, the American
Heart Association published a consensus statement addressing the
preoperative workup and treatment of patients undergoing noncardiac surgery.
22 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r22>  Subsequently, 2
major studies 14 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r14> ,
15 <http://archsurg.ama-assn.org/issues/v136n3/rfull/#r15>  have reported
the beneficial effect of perioperative beta-adrenergic blockade on the
reduction of cardiovascular events. On review, we therefore offer the
following specific recommendations for patients undergoing major elective
noncardiac surgery:
1. Identify patients at high risk: Most of this information can be obtained
through the history and physical examination. A 12-lead electrocardiogram
and basic laboratory tests to assess anemia, renal function, and glucose
tolerance cover most other risk factors. Although it is tempting to obtain a
functional study (such as a stress echocardiogram), preoperative myocardial
revascularization is currently indicated only in patients who exhibit
well-accepted criteria for coronary artery bypass (such as unstable angina).
2. Continue or initiate beta-adrenergic blockade: If men older than 40 years
and women older than 45 years are already taking a beta-adrenergic blocking
agent, continue therapy with a goal of lowering heart rate and systolic
blood pressure to 70 bpm and 110 mm Hg, respectively. If the patient is not
taking a beta-adrenergic blocking agent, begin an oral regimen as early as
possible preceding the scheduled surgery to achieve the previously stated
hemodynamic goals. The optimal beta-adrenergic blocking agent remains
unclear; however, a cardioselective agent (such as atenolol or metoprolol)
is likely the best choice.
3. Continue beta-adrenergic blockade throughout hospitalization: In the
absence of bradycardia (heart rate <60 bpm) and hypotension (systolic blood
pressure <100 mm Hg), judicious use of intravenous and oral beta-adrenergic
blocking agents should be continued after surgery, with a target heart rate
of 70 bpm and systolic blood pressure of 110 mm Hg.
4. Continue beta-adrenergic blockade as an outpatient: Although in the study
by Poldermans et al 15
<http://archsurg.ama-assn.org/issues/v136n3/rfull/#r15>  patients were
administered bisoprolol for only 30 days, many cardiologists recommend more
prolonged therapy. For reasons that remain unclear, protection against
cardiovascular events seems to extend beyond the period of direct adrenergic
inhibition.



Author/Article Information


From the Division of Cardiothoracic Surgery, Department of Surgery,
University of Colorado Health Sciences Center, Denver.

Corresponding author and reprints: Craig H. Selzman, MD, Division of
Cardiothoracic Surgery, Box C-310, University of Colorado Health Sciences
Center, 4200 E Ninth Ave, Denver, CO 80262.
This study was supported by grants from the Pacific Vascular Research
Foundation (Dr Selzman) and by grants GM49222 and GM08315 from the National
Institutes of Health, Bethesda, Md (Dr Harken).




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Edward E. Rylander,M.D.
    D.A.B.F.P. AND D.A.B.P.M.